There are two primary mechanisms by which high intensity focused ultrasound (HIFU) can ablate tissue. One is mechanical and due to cavitation. The other is thermal, via hyperthermia and boiling, due to the rapid temperature increase from absorption of ultrasound. Cavitation-based tissue ablation, referred to as histotripsy, offers promising opportunities for noninvasive treatment of tumors, as well as neonates with hypoplastic left heart syndrome (HLHS). The only treatment currently available for neonates is cardiac catheterization and balloon atrial septostomy, which must be performed within 2 weeks of birth. The morbidity and mortality rate associated with this procedure is as high as 50%. The advantage of histotripsy is its ability to provide tissue ablation with sharply demarcated boundaries. Recent investigations of controlled ultrasonic tissue ablation performed at the University of Michigan by Dr. Charles Cain and coworkers showed that tissue segments can be excised precisely, as required for HLHS treatment to perforate the atrial septum. The challenge is to keep the cavitation and therefore tissue ablation under control. Cavitation is a complicated phenomenon that depends on many factors such as ultrasound intensity, pulse duration and repetition frequency, properties of the surrounding medium, and presence of bubble nuclei. Understanding this complex process is necessary for practical and clinical applications of cavitation-based ultrasound methods. However, not only is there no model currently being used to describe cavitation cluster dynamics involved in histotripsy, but it is also not clear how boiling competes with cavitation in the process of tissue ablation. Recent experiments at the University of Washington by Dr. Vera Khokhlova and coworkers suggest that tissue ablation in gel occurs only following the creation of bubbles by boiling, rather than by cavitation. Whether tissue erosion is due to cavitation or boiling, complicated bubble dynamics are involved. The principal objective of the proposed research is to develop a mathematical model starting with the investigators'existing formalism for cavitation cluster dynamics in shock-wave lithotripsy. Our model permits analysis of interacting bubble dynamics accounting for pulsation, translation, coalescence, and rectified diffusion. Bubble interaction with tissue will be analyzed using a modification of the model that describes bubble growth and collapse near a tissue interface. Stresses in the tissue caused by shock waves and jets emitted during collapse will be estimated. Tissue heating and ultimately boiling due to hyperthermia associated with shock-enhanced absorption will be modeled to determine the role of thermal effects in histotripsy. Aspects of the model will be checked via comparison with measurements in ongoing experiments made available to us by our consultant Dr. Khokhlova. The long-term goal of the project is to provide a mathematical model that clarifies the underlying physics of ablative ultrasound technologies based on cavitation and also hyperthermia, and thus aids in modifying protocols for improving the efficacy of these new procedures. PUBLIC HEALTH RELEVANCE: Histotripsy is the name given to sharply demarcated fragmentation and removal of tissue by high intensity ultrasound used to produce localized cavitation bubble activity. It has been proposed as a new ablative technology that can be applied to noninvasive treatment of tumors and neonates with hypoplastic left heart syndrome. Our project will develop the mathematical foundation required to model this process and aid in increasing its efficacy through control of the cavitation and other physical mechanisms contributing to tissue ablation.